Distinctive characteristics and functions of multiple mitochondrial Ca2+ influx mechanisms

Intracellular Ca(2+) is vital for cell physiology. Disruption of Ca(2+) homeostasis contributes to human diseases such as heart failure, neuron-degeneration, and diabetes. To ensure an effective intracellular Ca(2+) dynamics, various Ca(2+) transport proteins localized in different cellular regions have to work in coordination. The central role of mitochondrial Ca(2+) transport mechanisms in responding to physiological Ca(2+) pulses in cytosol is to take up Ca(2+) for regulating energy production and shaping the amplitude and duration of Ca(2+) transients in various micro-domains. Since the discovery that isolated mitochondria can take up large quantities of Ca(2+) approximately 5 decades ago, extensive studies have been focused on the functional characterization and implication of ion channels that dictate Ca(2+) transport across the inner mitochondrial membrane. The mitochondrial Ca(2+) uptake sensitive to non-specific inhibitors ruthenium red and Ru360 has long been considered as the activity of mitochondrial Ca(2+) uniporter (MCU). The general consensus is that MCU is dominantly or exclusively responsible for the mitochondrial Ca(2+) influx. Since multiple Ca(2+) influx mechanisms (e.g. L-, T-, and N-type Ca(2+) channel) have their unique functions in the plasma membrane, it is plausible that mitochondrial inner membrane has more than just MCU to decode complex intracellular Ca(2+) signaling in various cell types. During the last decade, four molecular identities related to mitochondrial Ca(2+) influx mechanisms have been identified. These are mitochondrial ryanodine receptor, mitochondrial uncoupling proteins, LETM1 (Ca(2+)/H(+) exchanger), and MCU and its Ca(2+) sensing regulatory subunit MICU1. Here, we briefly review recent progress in these and other reported mitochondrial Ca(2+) influx pathways and their differences in kinetics, Ca(2+) dependence, and pharmacological characteristics. Their potential physiological and pathological implications are also discussed.